Probing enzymes late in the trypanosomal glycosylphosphatidylinositol biosynthetic pathway with synthetic glycosylphosphatidylinositol analogues.
Glycosylphosphatidylinositol (GPI)-anchored proteins are abundant in the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness in humans and the related disease Nagana in cattle, and disruption of GPI biosynthesis is genetically and chemically validated as a drug target. Here, we examine the ability of enzymes of the trypanosomal GPI biosynthetic pathway to recognize and process a series of synthetic dimannosyl-glucosaminylphosphatidylinositol analogues containing systematic modifications on the mannose residues. The data reveal which portions of the natural substrate are important for recognition, explain why mannosylation occurs prior to inositol acylation in the trypanosomal pathway, and identify the first inhibitor of the third alpha-mannosyltransferase of the GPI biosynthetic pathway.
Urbaniak
Michael D
MD
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Yashunsky
Dmitry V
DV
Crossman
Arthur
A
Nikolaev
Andrei V
AV
Ferguson
Michael A J
MA
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D017261:Glycosylphosphatidylinositols / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry*; D006801:Humans; D008364:Mannosyltransferases / Q000037:antagonists & inhibitors*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy
D004791:Enzyme Inhibitors; D017261:Glycosylphosphatidylinositols; D014344:Trypanocidal Agents; D008364:Mannosyltransferases